Conformance Rules how to follow and comply when specified by multiple sources?

Transcription

1 Conformance Rules 05-Nov Conformance Rules how to follow and comply when specified by multiple sources? PhUSE EU Connect 2018 Francis Dsa

2 Agenda Conformance Rules 05-Nov Different sources and specifications Our process and approach Scenario 1 Scenario 2 Global Standard Team vs Trial vs Project Conclusion

3 Conformance Rules 05-Nov Different sources and specifications 68 2 Validation/Conformance Rules FDA Validation Rules PMDA Validation Rules FDA Technical Rejection criteria CDISC SDTM Conformance Rules FDA Business Rules FDA Validation Rules 163 PMDA Validation Rules 667 SDTM Rules 326 Define-XML Rules 105 ADaM Rules 236 FDA Technical Rejection criteria 2 CDISC SDTM Conformance Rules 410 Programmable 356 non-programmable 54 FDA Business Rules 68 Clinical and Nonclinical 33 Clinical Only 21 Nonclinical Only 14 Challenges There are no mappings between the different sources of Validation/Conformance rules and the numbers do not match in the tool provided by vendors. There are also a number of conflicting rules between the different sources that is a challenge for sponsors as well as vendors.

4 Process Monitor requirements on clinical research and to prepare/implementation of new external standards. Conformance Rules 05-Nov Focus Group SDTM Global Standards Team Maintain SDTM Global Standards and ensure consistent use. SDTM _nn01 3.2_nn02 3.2_nn03 3.2_nn04 Project Standards Teams

5 Our approach Handling of Conflicting Rules Conformance Rules 05-Nov At Novo Nordisk, we have created a document called Novo Nordisk SDTMIG where we document the decisions taken on conflicting rules and clarify how they should be implemented consistently. This is controlled and maintained by a SDTM Global Standards Team. This team also monitors and reviews new standards and raises clarifying questions and comments to regulatory agencies and standards organisations. Novo Nordisk SDTMIG:

6 Our approach Conformance Checks Conformance Rules 05-Nov Based on the submission learnings from our peers, we now run conformance checks with multiple configuration files in different versions of Pinnacle 21 for FDA and PMDA. Structural checks on define.xml are done by SAS Clinical Standards Toolkit. In addition to SDTM data, conformance/consistency checks are conducted on Define.xml as well as between SDTM and ADaM.

7 Our approach Documenting in SDRG Conformance Rules 05-Nov Within our Study Data Reviewer s Guide (SDRG) template, we have added sub-sections for each set of conformance checks. Pinnacle 21 Justification database This is how we manage common issues

8 Conformance Rules 05-Nov Scenario 1 ARM/ARMCD and ACTARM/ACTARMCD CDISC ARM/ARMCD and ACTARM/ACTARMCD are required variables Required variables must always be included in the dataset and cannot be null for any record FDA Screen failures, when provided, should be included as a record in DM with the ARM field left blank. For subjects who are randomized in treatment group but not treated, the planned arm variables (ARM and ARMCD) should be populated, but actual treatment arm variables (ACTARM and ACTARMCD) should be left blank.

9 Our approach Handling of Conflicting Rules We have decided to follow the CDISC guidelines (we also prefer non-blank values). This is documented in our Novo Nordisk Interpretation of SDTM IG. Conformance Rules 05-Nov Screenshot from Novo Nordisk SDTMIG:

10 Conformance Rules 05-Nov Scenario 2 ELEMENT and ETCD Based on 2011 CDER Common Data Standards Issues Document, FDA desired inclusion of ELEMENT and ETCD (element code) to help reviewers understand timing of events. However, in all later FDA published Study Data Technical Conformance Guide up to V4.1 published in 2018, only EPOCH is required. FDA validator rules version 1.2 published in December 2017 still mentions that variables requested by FDA in Policy documents should be included in the dataset, e.g. EPOCH and ELEMENT.

11 Our approach Handling of Conflicting Rules Screenshot from Novo Nordisk SDTMIG: Conformance Rules 05-Nov We are following the FDA guidelines for last 6 years. This is documented in our Novo Nordisk Interpretation of SDTM IG. SDTM Global Standards team is currently discussing with our stakeholders Biostatistics and Risk Based Monitoring about removal of ETCD and ELEMENT. When do we remove it?

12 Our approach Documenting in SDRG Conformance Rules 05-Nov Within our Study Data Reviewer s Guide (SDRG) template, we have explained it.

13 Conformance Rules 05-Nov Global Standard Team vs Trial vs Project Change process Global Standard Team and requirements: Requirements and conformance rules are moving targets. It evolves over time based on the past learning. Versioning is the way to get around the new requirements and rules. Training and guidance document(nn Interpretation of SDTMIG) is the key so we implement the requirements the same way. Trial team and the project team: The trial likes to use the latest model and the tool versions. However if the trial is one of the last one for the submission package then they would like to follow the rest of the trials to enable pooling for Submission. Meeting with agency is fruitful. We send representative both from Project and the Standard Team to clarify/confirm implementation of requirements.

14 Conclusion Conformance Rules 05-Nov Multiple requirements for conformance rules exist from different regulatory agencies and tools versions. It is important to run all of the current available conformance rules to ensure that all issues are managed and addressed. All identified issues and justifications are described in respective subsections in the SDRG which enables global submissions.

15 Thank you Conformance Rules 05-Nov Francis Dsa Principal Standards Specialist Clinical Data Standards Novo Nordisk A/S